A Multicenter Randomized Phase IIb Efficacy Study of Vx-001, a Peptide-Based Cancer Vaccine as Maintenance Treatment in Advanced Non–Small-Cell Lung Cancer: Treatment Rationale and Protocol Dynamics

doi:10.1016/j.cllc.2013.02.001

Clinical Lung Cancer

Volume 14, Issue 4, July 2013, Pages 461-465

https://doi.org/10.1016/j.cllc.2013.02.001 Get rights and content

Abstract

We present the treatment rationale and study design of a multicenter, open-label, randomized, 2-arm, phase IIb study. Patients with stage IV or recurrent stage I to III non–small-cell lung cancer (NSCLC) whose disease does not progress after 4 cycles of first-line platinum-based chemotherapy will be randomized in a 1:1 ratio to 1 of 2 study arms. Patients will receive the cancer vaccine Vx-001 + Montanide ISA51 VG (Seppic, Paris, France) adjuvant subcutaneously, at a dose of 2 mg, or placebo + Montanide ISA51 VG adjuvant subcutaneously. The vaccination protocol comprises 2 injections with the TYR-Vx001 or placebo (1 at day 0 and another at week 3) and 4 injections with the ARG-Vx001 or placebo, at weeks 6, 9, 12, and 15. After the treatment assessment at week 18, patients will receive the ARG-Vx001 or placebo every 12 weeks starting from week 27 until disease progression, unacceptable toxicity, withdrawal of informed consent, or death. The primary end point of this study is the survival rate at 12 months. Secondary end points include time-to-event comparison of overall survival and comparison of time to treatment failure. Exploratory objectives include comparison of disease control rate after the end of subsequent second-line treatments, comparisons of vaccine immune responses, comparison of survival rate at 12 months in patients with vaccine-induced immune response detected after the second and sixth injections, identification of biomarkers on lymphocytes and on tumors, and comparison of safety and tolerability.

Section snippets

Rationale

Non–small-cell lung cancer (NSCLC), including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, is the most common type of lung cancer, representing about 80% of lung cancer cases; it accounts for approximately 1.2 million new cases annually worldwide.¹ Because most patients have advanced disease at diagnosis, systemic therapy, including chemotherapy and new targeted agents, is the mainstay of management. The same approach is also reserved for distant recurrent stage I to stage

Objectives

The primary end point of the present study is to compare survival rates at 12-months in Vx-001-treated and placebo-treated patients. The secondary end points include time-to-event comparison of OS and comparison of time to treatment failure in Vx-001-treated and placebo-treated patients. The exploratory objectives are comparison of DCR after the end of subsequent second-line treatments and comparison of vaccine-induced immune responses in terms of frequency of TERT- specific interferon-γ and

Eligibility Criteria

Study entry is limited to patients aged ≥ 18 years of age with histologically or cytologically confirmed stage IV NSCLC as defined by the International Association for the Study of Lung Cancer Lung Cancer Staging Project (seventh edition)²² or distant recurrent stage I to III disease at least 6 months after resection, after the end of adjuvant chemotherapy, or after standard locoregional treatment as defined by the American College of Chest Physicians.² Other requirements include patients

Treatment Plan

This international multicenter phase II study will be conducted according to a double-blind placebo-controlled randomized (1:1 ratio) design (Figure 1). Patients who do not progress after 4 cycles of first-line platinum-based chemotherapy will be administered, at predefined visits, the Vx-001 + Montanide ISA51 VG adjuvant subcutaneously at a dose of 2 mg, or placebo + Montanide ISA51 VG adjuvant subcutaneously. The vaccination protocol comprises 2 injections with the TYR-Vx001 or placebo, 1 at

Expected Results and Toxicities

The sample size calculation for this trial is based on an 18-month recruitment period and minimum follow-up of 12 months. There will be no interim analysis for efficacy. Assuming that 70% of screened patients will experience DCR after first-line chemotherapy and 43% of screened patients will be HLA-A*0201 positive, of whom 80% will be TERT positive in their primary tumors, approximately 920 patients will be screened to enroll 220 patients (110 on the Vx-001 arm and 110 on the placebo arm), as

Analytical Methods

The primary analysis (full analysis set [FAS]) will be performed by a 1-sided Pearson χ² test of proportions to compare the survival rate of the Vx-001-treated group with the placebo-treated group at 12 months. A patient with OS (success) at 12 months is defined as a patient who is alive as confirmed by the visit at week 52. If the patient misses the visit or has been lost to follow-up, every effort will be made by the investigator to ascertain whether the patient was alive on the theoretical

Conclusion

The present trial is designed to examine the efficacy and safety of Vx-001 vaccination vs. placebo in patients with stage IV or recurrent stage I to III NSCLC whose disease does not progress after 4 cycles of platinum-based induction chemotherapy. Patients will be randomized to receive either Vx-001 or placebo as maintenance treatment. Patients will be monitored and assessed throughout the duration of the study as described earlier. The primary end point of this study is survival rate at 12

Disclosure

Dr Vassilis Georgoulias, Dr Jean-Yves Douillard, Dr David Khayat, Dr Christian Manegold, Dr Rafael Rosell, and Dr Cesare Gridelli serve as consultants for Vaxon-Biotech. Dr Jeanne Menez-Jamet is an employee of Vaxon-Biotech and owns stock in Vaxon-Biotech. Dr Marina Ichè and Dr Kostas Kosmatopoulos own stock in Vaxon-Biotech. All other authors have stated that they have no conflicts of interest.

Acknowledgments

This study is sponsored by Vaxon-Biotech.

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Three hTERT vaccines i.e., GRNVAC1, GV1001 and Vx001 in cancer patients have recently been exploited to induce anti-telomerase immune responses [136]. GV1001 belongs to human leukocytes antigen class-II restricted hTERT peptide having 611–626 amino acid sequence of hTERT active site with granulocyte monocyte colony stimulating factor [137]. Processing of human leukocytes antigen class-I to achieve CD4+ and CD8+ responses, leads to the activation of strong Tc lymphocyte [138].
Telomerase plays a significant role to maintain and regulate the telomere length, cellular immortality and senescence by the addition of guanine-rich repetitive sequences. Chronic inflammation or oxidative stress-induced infection downregulates TERT gene modifying telomerase activity thus contributing to the early steps of gastric carcinogenesis process. Furthermore, telomere-telomerase system performs fundamental role in the pathogenesis and progression of diabetes mellitus as well as in its vascular intricacy. The cessation of cell proliferation in cultured cells by inhibiting the telomerase activity of transformed cells renders the rationale for culling of telomerase as a target therapy for the treatment of metabolic disorders and various types of cancers. In this article, we have briefly described the role of immune system and malignant cells in the expression of telomerase with critical analysis on the gaps and potential for future studies. The key findings regarding the secrets of the telomerase summarized in this article will help in future treatment modalities for the prevention of various types of cancers and metabolic disorders notably diabetes mellitus.
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Vx-001 is the first antitumor vaccine based on optimized cryptic peptides, targeting tumor antigen TERT. Vx-001 (Vaxon Biotech, Paris, France) is a low affinity cryptic TERT peptide (RLFFYRKSV) where its functional peptide is hidden inside the protein [5,24,25]. Vx-001 is composed of the 9-mer cryptic TERT572 peptide and its optimized variant TERT572Y (YLFFYRKSV) where first amino acid is replaced by tyrosine, which enhances its HLA-I affinity [23,26].
Telomerase is a Reverse Transcriptase that maintains the telomere length. It is absent in most somatic cells but is found in stem cells, germ cells and around 90% of cancers. It plays a crucial role in developing and maintaining cancer cells. Telomerase, a HLA class-I antigen, is able to stimulate cell mediated immune response by inducing cytotoxic T-cells. This property of telomerase is being exploited in targeting cancers by host’s own immune responses; stimulated by various Human Telomerase Reverse Transcriptase (hTERT) derived vaccines. Many approaches and studies including clinical trials have shown effective anticancer responses of these vaccines, without toxicity to non cancer cells. In this article we have compiled different hTERT based anticancer immunotherapy approaches, vaccines and their performances.
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Forty-six HLA-A*0201-positive patients with advanced NSCLC and residual (n = 27) or progressive (n = 19) disease following front-line treatment received two subcutaneous injections of the optimized TERT_572Y peptide followed by four injections of the native TERT₅₇₂ peptide, every 3 weeks. Peptide-specific immune responses were monitored by enzyme-linked immunosorbent spot assay at baseline, and after the 2nd and the 6th vaccinations. Thirty-eight HLA-A*0201-positive matched patients were used as historical controls.
Twenty-three patients (50%) completed the vaccination protocol and 87% received at least two administrations. Twelve patients (26%) without disease progression after the 6th vaccination received boost vaccinations. Three (7%) patients achieved a partial response and 13 (28%) disease stabilization. The disease control rate was significantly higher in patients with non-squamous histology compared to those with squamous-cell histology [n = 14 (45%) versus n = 2 (13%); p = 0.03]. The median progression-free survival (PFS) and overall survival (OS) was 3.8 (range, 0.7–99.4) and 19.8 months (range, 0.7–99.4), respectively. Patients who developed immune response had a numerically higher PFS compared to those who failed to mount any (6.7 versus 2.7 months; p = 0.090). However, the median OS for the immune-responders was significantly prolonged compared to non-responders (40.0 versus 9.2 months, respectively; p = 0.02). Toxicity was <grade 2.
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Current trial reportA Multicenter Randomized Phase IIb Efficacy Study of Vx-001, a Peptide-Based Cancer Vaccine as Maintenance Treatment in Advanced Non–Small-Cell Lung Cancer: Treatment Rationale and Protocol Dynamics

Abstract

Section snippets

Rationale

Objectives

Eligibility Criteria

Treatment Plan

Expected Results and Toxicities

Analytical Methods

Conclusion

Disclosure

Acknowledgments

Chest

Ann Oncol

Ann Oncol

Lancet Oncol

Cancer Treat Rev

Immunity

Ann Oncol

J Thorac Oncol

Cancer fact sheets: lung cancer 2008

Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer

N Engl J Med

J Clin Oncol

Current trial report
A Multicenter Randomized Phase IIb Efficacy Study of Vx-001, a Peptide-Based Cancer Vaccine as Maintenance Treatment in Advanced Non–Small-Cell Lung Cancer: Treatment Rationale and Protocol Dynamics